Functional MRI (fMRI) permits evaluation of distributed brain systems that encode incoming stimuli. It offers[unreadable] anatomic localization of neural activation, complementing the temporal resolution of electrophysiology. Most[unreadable] fMRI studies in schizophrenia have focused on fronto-temporal "executive" systems. However, evidence from[unreadable] the current CCNMD studies, consistent with an extensive ERP and a growing fMRI literature, indicate[unreadable] impaired activation and deficits in early stages of stimulus encoding. Current studies, and data from Project I,[unreadable] suggest abnormal alterations in gamma oscillations in schizophrenia, most consistently for induced gamma.[unreadable] Such abnormalities implicate deficits in coordinating activity in multiple regions that use phase locked[unreadable] gamma frequency oscillations. Gamma oscillations have lately been linked to hemodynamic signal changes[unreadable] in both the visual and the auditory modalities.[unreadable] The proposed project will combine homologous visual and auditory paradigms, in parallel with[unreadable] electrophysiology (Project I), to investigate early stages of stimulus encoding, focusing on integration. The[unreadable] dimensions of stimulus modality, the required integration (spatial, temporal or both), and the nature of[unreadable] controlled-processing demands (top-down vs. bottom-up), will be systematically manipulated. We will use[unreadable] event-related designs, in a high-field scanner (3 Tesla), to model the hemodynamic response for each[unreadable] stimulus class. Another new direction in the project will build on our genetic studies in schizophrenia. We[unreadable] have established that neurocognitive measures are potential endophenotypic markers of vulnerability present[unreadable] in unaffected family members. The sample will include 80 patients with schizophrenia, 80 first-degree[unreadable] unaffected family members and 80 unrelated healthy people. The CCNMD hypothesis will be tested by[unreadable] implementing a cascade of fMRI studies that capitalize on the complementarity between electrophysiology[unreadable] and fMRI. Parallel studies will be performed within the auditory and visual modalities and each participant will[unreadable] undergo both sensory conditions as well as the electrophysiologic studies described in subproject 0001. The[unreadable] cascade will trace the stages of information processing from stimulus deviance and novelty detection through[unreadable] encoding using adaptation to fMRI of standard electrophysiologic tasks that have been associated with[unreadable] specific components of the ERP. The neurobehavioral probes will examine regional activation induced by[unreadable] target detection, response to novelty and recognition memory. Physiological activity will be measured with[unreadable] the BOLD paradigm using event-related contrasts to help establish the stage of information processing in the[unreadable] cortico-thalamic network where patients show abnormal activation. Magnitude and spatial extent of activation[unreadable] will be related to: a. on-line performance for tasks requiring response, with both accuracy and reaction time[unreadable] available, b. Basal neurocognitive computerized measures obtained by Core A, which yield estimates of[unreadable] accuracy and speed for eight neurocognitive domains; c. clinical parameters assessed by Core A, which[unreadable] provide measures of symptoms, functioning and course. The targeted sampling by DTNBP1, NRG1 and[unreadable] RGS4 will permit linking activation abnormalities to vulnerability haplotype.